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Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis (ASTRO-CM)

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by University of Minnesota - Clinical and Translational Science Institute
Sponsor:
Collaborators:
Infectious Disease Research Institute
Mbarara University of Science and Technology
Ifakara Health Institute
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT01802385
First received: February 27, 2013
Last updated: November 19, 2014
Last verified: November 2014

February 27, 2013
November 19, 2014
August 2013
July 2017   (final data collection date for primary outcome measure)
Survival [ Time Frame: 18 weeks ] [ Designated as safety issue: Yes ]
18-week survival. The comparison will be between sertraline 400mg group and placebo
Early Fungicidal Activity [ Time Frame: 14 days ] [ Designated as safety issue: No ]
To determine whether adjunctive sertraline will lead to a faster rate of fungal clearance from cerebrospinal fluid (CSF), as measured by early fungicidal activity (EFA), compared to standard therapy alone.
Complete list of historical versions of study NCT01802385 on ClinicalTrials.gov Archive Site
  • Safety [ Time Frame: 18 weeks ] [ Designated as safety issue: Yes ]
    Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions)
  • Intolerance [ Time Frame: 18 weeks ] [ Designated as safety issue: Yes ]
    Time to dose-reduction for intolerance
  • Microbiologic [ Time Frame: 14 days ] [ Designated as safety issue: No ]
    2 week CSF culture sterility
  • Neurocognitive Performance [ Time Frame: 14 weeks ] [ Designated as safety issue: No ]
    Quantitative neurocognitive performance score (QNPZ-8) and Center for Epidemiologic Studies in Depression (CES-D) scale at 4 and 14 weeks.
  • Early Fungicidal Activity [ Time Frame: 14 days ] [ Designated as safety issue: No ]
    To determine whether adjunctive sertraline will lead to a faster rate of fungal clearance from cerebrospinal fluid (CSF), as measured by early fungicidal activity (EFA) of clearance of the Cryptococcus colony forming units (cfu) per mL of CSF per day, compared to standard therapy alone.
  • IRIS and Relapse Incidence [ Time Frame: 18 weeks ] [ Designated as safety issue: Yes ]
    Cumulative incidence of central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse
  • Event free survival [ Time Frame: 18 weeks ] [ Designated as safety issue: Yes ]
    Event free survival of composite events of: death,central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse.
  • Safety [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
    Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions)
  • Intolerance [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
    Time to dose-reduction for intolerance
  • Survival [ Time Frame: 10 weeks ] [ Designated as safety issue: Yes ]
    10-week survival time
  • Microbiologic [ Time Frame: 14 days ] [ Designated as safety issue: No ]
    2 week CSF culture sterility
  • Neurocognitive Performance [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Quantitative neurocognitive performance score (QNPZ-8) and Center for Epidemiologic Studies in Depression (CES-D) scale at 4 and 12 weeks.
  • Cost analysis [ Time Frame: 18 weeks ] [ Designated as safety issue: No ]
    Cost-benefit of adjunctive sertraline therapy
  • Switching to Open Label Sertraline [ Time Frame: 14 weeks ] [ Designated as safety issue: Yes ]
    Incidence of switching from blinded to open-labeled study drug due to severe depression occurring between 4 to 14 weeks.
Not Provided
 
Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis
Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis

This is a phase III trial to determine whether adjunctive sertraline will lead to improved survival 18-week survival.

There is an initial phase I/II unmasked dose finding pharmacokinetic study of CSF concentrations in at least 20 persons.

This is a phase III randomized trial to evaluate whether sertraline when added to standard amphotericin-based therapy for cryptococcal meningitis, will lead to improved survival . Cryptococcal meningitis diagnosis will be made via CSF cryptococcal antigen (CRAG) at time of lumbar puncture (LP) with confirmation by CSF culture. After informed consent, subjects that meet eligibility requirements will be able to enter study. A non-randomized phase I dose-escalation study will first be conducted to help optimize dosing for a larger randomized phase II study.

Phase I/II Design: In addition to standard induction therapy for cryptococcal meningitis, subjects will receive increasing doses of sertraline in a dose-escalation study design. The first subjects enrolled into the study will receive 100 mg/day of sertraline. This dose will be sequentially increased by 100 mg/day in groups of n=5 up to a maximum of 400mg daily. Total anticipated enrollment: 100 subjects.

Phase III Design: Subjects will be randomized to standard induction therapy with masked placebo or sertraline at 400mg/day. We will use a permutated block randomization in a 1:1 allocation (n=225 per arm). Total anticipated enrollment: 450 subjects.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Cryptococcal Meningitis
  • Fungal Meningitis
Drug: Sertraline
Other Names:
  • Zoloft
  • Lustral
  • Placebo Comparator: Placebo
    Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day).
  • Experimental: Sertraline 400mg
    Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks.
    Intervention: Drug: Sertraline
Zhai B, Wu C, Wang L, Sachs MS, Lin X. The antidepressant sertraline provides a promising therapeutic option for neurotropic cryptococcal infections. Antimicrob Agents Chemother. 2012 Jul;56(7):3758-66. doi: 10.1128/AAC.00212-12. Epub 2012 Apr 16.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
450
July 2017
July 2017   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Cryptococcal meningitis diagnosed by CSF cryptococcal antigen (CRAG)
  • HIV-1 infection
  • Ability and willingness of the participant or legal guardian/representative to provide informed consent
  • Willing to receive protocol-specified lumbar punctures

Exclusion Criteria:

  • Age < 18 years
  • Receipt of >=3 doses of amphotericin therapy
  • Cannot or unlikely to attend regular clinic visits
  • History of known liver cirrhosis
  • Presence of jaundice
  • Pregnancy
  • Current breastfeeding
Both
18 Years and older
No
Contact: David B Meya, MBChB MMed david.meya@gmail.com
Contact: David R Boulware, MD MPH boulw001@umn.edu
Tanzania,   Uganda
 
NCT01802385
S4 0296-01, R01NS086312-01
Yes
University of Minnesota - Clinical and Translational Science Institute
University of Minnesota - Clinical and Translational Science Institute
  • Infectious Disease Research Institute
  • National Institute of Neurological Disorders and Stroke (NINDS)
  • Mbarara University of Science and Technology
  • Ifakara Health Institute
Principal Investigator: David B Meya, MBCHB MMed Infectious Disease Institute
Study Director: Joshua Rhein, MD University of Minnesota - Clinical and Translational Science Institute
Study Chair: David R Boulware, MD MPH University of Minnesota - Clinical and Translational Science Institute
University of Minnesota - Clinical and Translational Science Institute
November 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP